The transcription factor NF-E2 p45-related factor 2 (Nrf2) mediates adaptation to oxidative stress by inducing cytoprotective genes including heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1). Nrf2 is principally controlled by Kelch-like ECH-associated protein 1 (Keap1), which allows constitutive ubiquitylation and rapid degradation of Nrf2 by the cullin-3 (Cul3)-RING ubiquitin ligase CRLKeap1 under non-stressed conditions. Simultaneously, glycogen synthase kinase-3 (GSK-3) also negatively controls Nrf2 through phosphorylation of a DSGIS-containing destruction motif in Nrf2, which then allows binding by β-transducin repeat-containing protein (β-TrCP) and ubiquitylation of the transcription factor by the Skp1−Cul1−F-box (SCF) ubiquitin ligase designated SCFβ-TrCP. It is well documented that oxidative stressors activate Nrf2 by antagonizing Keap1. We now show that both tert-butyl hydroquinone (tBHQ) and diethyl maleate (DEM), but not sulforaphane, induce Hmox1 and Nqo1 in Keap1−/− mouse embryonic fibroblasts (MEFs). Moreover, expression of Hmox1 and Nqo1 in Keap1−/− MEFs is substantially blunted by inhibition of either phosphoinositide 3-kinase (PI3K, using LY294002) or protein kinase B (PKB/Akt, using MK-2206), whereas inhibition of GSK-3 (using CT99021) induces expression of Hmox1 and Nqo1. Herein, we provide evidence that Nrf2 is subject to repression by both Keap1 and the axis between GSK-3 and β-TrCP. One likely scenario is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN caused by tBHQ and DEM results in an increase in the levels of PIP3 produced by PI3K, and hence 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity, which then stimulates PKB/Akt signaling.